Semaglutide vs. Tirzepatide: A Doctor's Honest Comparison

Semaglutide or tirzepatide? Ozempic or Mounjaro? It's the most asked question in GLP-1 medicine, and Dr. Clete Barrick has prescribed both to over 5,000 patients.

In this episode, he covers the real differences between single and dual agonist medications, the head-to-head SURMOUNT-5 trial results, side effect profiles (including the birth control interaction most providers miss), who actually does better on which medication, and why the best GLP-1 is the one you can afford to stay on.

He also addresses compounding costs, why semaglutide is sometimes the smarter pick despite tirzepatide's stronger averages, the oral Wegovy option for patients with needle phobia, and the fear-mongering around FDA regulatory moves that's driving patients to make bad decisions.

In this episode:

• Single vs. dual agonist: what the mechanism difference actually means
• SURMOUNT-5 and the 2026 Bernardi meta-analysis (28 trials, 34,000 patients)
• Why averages hide a massive spread in individual responses
• GI side effects compared (and why tirzepatide is often better tolerated)
• The birth control absorption warning (59% reduction with tirzepatide)
• Autoimmune conditions, migraines, and PCOS: which medication has the edge
• Compounding costs: semaglutide vs. tirzepatide pricing reality
• The sledgehammer vs. Michelangelo analogy
• Why you shouldn't switch medications based on social media fear

New episodes weekly. Subscribe and visit barrickhealth.com for physician-led GLP-1 care.

Everything discussed in this episode is education, not medical advice for your specific situation. Talk to your prescriber before making changes to your treatment.

LINKS: barrickhealth.com https://www.youtube.com/@BarrickHealth

REFERENCES CITED:

• Jastreboff AM, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5). N Engl J Med. 2025.
• Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021;384:989-1002.
• Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387:205-216.
• Lincoff AM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT). N Engl J Med. 2023;389:2221-2232.
• Bernardi S, et al. Network meta-analysis of tirzepatide vs semaglutide (28 RCTs, 34,367 patients). J Diabetes. 2026.
• Mounjaro prescribing information: oral contraceptive absorption interaction data.

Transcript

SPEAKER_00 0:01

Which one should I take? Ozempik or Manjaro? I get this question every single day. In my inbox, in my exam room, in my DMs. And the answer is not what most of the internet tells you. It's not terzepatite is better, end of discussion. It's not. They're basically the same. I'm Dr. Cleet Berick, dual board certified in internal medicine and obesity medicine. I've treated thousands of patients on GLP1 medications, peptides, and medical weight loss therapy. This is Street Shot, the science of weight loss explained by a doctor who lives it. Quick note everything on this show is for education only. It is not medical advice for your specific situation. Always talk to your prescribing physician before making any changes to your treatment. Welcome to Street Shot. I have prescribed both of these medications to countless patients. I've watched patients thrive on semaglutide, you've stalled on terzepitide, and I most certainly have watched the reverse. I have a framework for deciding which one to start with that goes beyond the one with more weight loss wins. Important note up front: this entire episode is framed around weight loss. If you're here because you're trying to decide between these medications for weight management and you don't have type 2 diabetes, this episode is built for you. We'll touch on diabetes where it's relevant, but the framework today is about the obesity indication. By the end of this episode, you'll know the trial data, the side effect differences, the cost, math, and the one drug interaction that most providers miss entirely. Fair warning. If you came here expecting me to pick a winner, I'm gonna disappoint you. Then I'm going to give you something much better. Last episode I explained how GLP1 medications amplify a hormone your body already makes. Semaglutide does that by activating one receptor, GLP1. It's a single agonist medication. Trzepatide activates two receptors, GLP1 and GIP, the glucose-dependent insulinotropic polypeptide. It's a dual agonist, two hormones, two receptor systems working simultaneously. Think of it like air conditioning. Semaglutide is a powerful single unit AC. Trzepatide is a dual zone system that cools the house from two different directions at once. So both will cool the house. The dual system tends to be more efficient. GIP was actually controversial when trzeptide was first developed. So some researchers weren't sure whether adding the GIP signaling would help or hurt. The clinical trial data settled that argument. So let's talk numbers. The landmark trial for semaglutide was step one. Patients on semaglutide, 2.4 milligrams, lost an average of 14.9% of their body weight over 68 weeks. For a 250-pound person, that's about 37 pounds. The landmark trial for terzepatide was Surmount 1. Patients on the highest dose, 15 milligrams, lost an average of 22.5% of their body weight over 72 weeks. So for that same 250-pound individual, that would be about 56 pounds. Then came the head-to-head. That was a Surmount 5 trial published in the New England Journal of Medicine in 2025. It directly compared terasepatide to semaglutide. Same patients, randomized 72 weeks. So trzepatide won by about 6.5 percentage points, which is roughly 15 more pounds for the average patient. Those numbers matter, uh, but here's what you need to understand about averages. So you know they hide a massive spread in step one. About half of patients lost 15% or more, but roughly 12 to 15% didn't even hit 5%. Uh in Samount 1, 57% hit 20% weight loss at the highest dose. So those are better numbers, but there's still a bell curve. Some patients do phenomenally well on semaglutide, and some patients struggle on terzeptide. The averages tell you which medication performs better across a population. So they don't tell you which one will work better for your specific body. That's the N of 1 principle from episode 1. 2026 network meta-analysis by Bernardi and colleagues, pooling 28 RCTs, randomized controlled trials, over 34,000 patients confirmed terzepatide superiority on weight reduction, BMI, waste circumference, A1C, and fasting glucose. So the data is pretty consistent. On average, terzepatide does outperform. GI side effects are the main event for both medications. Nausea, diarrhea, vomiting, constipation. Both cause them, but the profiles are not identical. In the STEP trials, 44% of semiglutide patients reported nausea at some point during the treatment, whereas in SRMAT1, the nausea rate uh ranged with trusepatide from 25 to 31%, depending on the dose. So that is a meaningful difference. And multiple trials and real-world data sets suggest trzepatide is somewhat better tolerated on the GI front for many, if not most, patients. There is a wrinkle. Truseptide slows gastric emptying more aggressively than semaglutide, especially during the first weeks at each new dose. So that does have some practical implications. The biggest one is you know trzepatide can reduce the absorption of oral contraceptives by up to 59% for peak concentration. Semaglutide doesn't do this to a clinically significant degree. So that's a critical point for listeners. If you're on birth control pills and you're starting trzepatide, gotta use backup contraception during the first four weeks at each new dose. This is in the prescribing information, and unfortunately, it does get missed pretty consistently by a lot of prescribers. Trzepatide also appears to cause more of the delayed gastric emptying that shows up on pre-surgical testing, which matters for the anesthesia conversation we'll cover in a future episode. For both medications, over 95% of GI side effects are mild to moderate. Over 95% of patients can continue treatment. The side effects do tend to cluster during dose increases in fade once you stabilize. Now let's talk hair loss. So this comes up constantly, especially on Reddit. Let me give you my honest take. So I do not believe hair loss is caused by these medications directly. In my clinical experience, hair shedding tracks with the rate and amount of weight loss, not the specific drug. You don't lose 50 pounds a little too quickly on either medication. Your body may shift hair follicles into a resting phase. So that's called telogen fluvium. It's temporary and it happens with any rapid weight loss, including bariatric surgery. I want to be transparent. That's my clinical opinion. Trial data shows slightly higher hair loss rates with trusepatide, usually about 5% in trials versus semaglutide, which is around 3%. But trzepatide also produces more weight loss. So, which to me, that is the more likely explanation. We'll go deeper on hair loss and body composition in future episodes. One more thing before we move on. Mental health. You may have seen headlines about GLP1s and depression or suicidal thoughts. Here's what the data actually shows. So pharmacovigilance analysis of adverse event databases have found a signal for depression and suicidal ideation with semaglutide specifically, but not with trzepatide. So a 2025 FAIRS analysis found a reporting odds ratio of about 1.9 for depression with semaglutide. Terzepatide showed significantly lower rates and no signal above the background. A post hoc analysis of the surmount trials published in 2026 found truse had favorable psychiatric safety overall. So to be clear, you know, these are pharmacovigilance signals, not proof of causation. The absolute rates are low for both medications. But if you have a history of depression or anxiety, it's worth discussing with your prescriber. In my own practice, I've occasionally seen mild anxiety, maybe a little bit more with trasepatide, but it's rare. And I do think overall I see more depression with semiglutide. The bigger point is you know, pay attention to your mood on either medication and definitely tell your doctor if something changes. Here's my prescribing framework. So trzepatide is first line for most new patients. Stronger average weight loss, dual mechanism, better GI tolerability. If a patient has type 2 diabetes or significant insulin resistance, trosepatide has an edge because that GIP effect also improves insulin sensitivity through an additional pathway besides just GLP1 alone. Semaglutide is preferred when, well, let's be honest, when insurance covers Ozempic or Wagovi, but not Zapbound or Manjaro. This is a pretty common situation I see. Uh, in other situations, so that the patient is on an oral contraceptive and wants to avoid the absorption issue. The patient has established cardiovascular disease. So, you know, semaglutide has the select trial showing about a 20% reduction in major cardiac events. So trzezepatide's cardiovascular outcome trial is still running. Or, you know, the patient who is already succeeding on semaglutide. There's no clinical reason to switch. Stick with what's working. That's a common thread on things. So for women with PCOS, I do lean terzepatite. Anecdotally, you know, my PCOS patients do better on it, and the early data is starting to back this up. 2025 study of women with PCOS on terzepatide showed irregular menstrual cycles dropped from 86% all the way down to 32%. You know, insulin resistance improved significantly. And a real-world study presented at Obesity Week 2025 found over 90% of PCOS patients hit at least a 10% weight loss within 10 months. There is even a clinical trial now registered, specifically testing terzepatide for PCOS. So the dual mechanism targeting insulin resistance, the theoretical reason this works and the clinical picture is consistent with that theory. So we don't have a large randomized trial yet, but for my PCOS patients, you know, trzepatide is generally where I start. And for what it's worth, you know, my prediction is sometime in the next couple of years it will likely be FDA approved for treatment of PCOS, but that is far in the future, unfortunately, I believe. Two more situations where I lean trzepatide. So, you know, patients with autoimmune conditions and patients with migraines. Umrzepatide appears to have a stronger anti-inflammatory effect uh than semaglutide. The GIP pathway has some distinct effects on inflammatory signaling that GLP1 alone just doesn't fully replicate. For my patients with autoimmune conditions, I've seen terzepatide, you know, make a pretty impressive and noticeable difference in a lot of their inflammatory burden beyond just what weight loss alone would explain. You know, migraines are a similar story in my clinical experience. Terzepatide seems to reduce migraine frequency more effectively than semaglutide. Again, I want to be clear, this is based on what I'm seeing in my practice, not on published randomized trials. The research on GLP1s and migraines is still early. It's intriguing, but the pattern has been consistent enough across my patients that it factors into my prescribing decisions. So if you're a migraine sufferer weighing these two medications, again, worth a conversation with your doctor. GI tolerability is also a big part of why terzepatide works for so many patients. It's not just the trial numbers I mentioned earlier. Uh, in practice, patients on terzepatide report less nausea, less vomiting. Fewer of those early weeks where you feel like you can't eat anything without regretting it. If a patient has a history of a sensitive stomach where they're anxious about the side effects they're, you know, they've read about online, terzepatide generally gives us a smoother ride more often than not. Quick note on muscle loss, um, because I'm I know this has been on everybody's mind and rightfully so. Early data does seem to suggest terzeptide may preserve a little bit more you know lean mass than semiglutide during the weight loss phase. This needs more research. Um, we'll do a deep dive on body composition, protein, and resistance training in a future episode, but it's another point in terzepatide's column for patients worried about losing muscle along with the fat. Quick aside, I see this question quite a bit online. So, you know, can I take a low dose of both? Uh no. There's zero data supporting combining semaglutide and terzepatide. None. Uh we're a data-driven practice, and when there's no data, we don't experiment on patients. So this is actually where the rare horror stories seem to come from. There was a case last year where one was prescribed both medications by different doctors that didn't know each other, and I believe it led to a very serious adverse event. I remember reading on that uh in some of the mainstream news outlets. Stacking GLP1 agonists, you know, it creates additive receptor stimulation that can cause some very severe GI complications. One medication at a time, if it's not working, we switch, we don't stack. Now let's talk about the elephant in the room cost money, money, money, specifically in the compounding world. So let's be real. You know, a huge number of patients aren't on compounded GLP1s. That's the reality of this market right now. Uh, and if you're paying out of pocket at a compounding pharmacy, semaglutide is almost always cheaper than trzepatide. You know, sometimes by a lot, uh compounded trasepatide can run two, three, sometimes four times as much what compounded semaglutide costs, you know, depending on the pharmacy and the dose. The best medication in the world doesn't work if you can't afford to stay on it. Trzepatide is a financial stretch, and the choice is between trzepatide for three months or semaglutide for a year. Semaglutide wins that math every time. You know, consistency beats potency. The medication you can actually take every week for the long haul is the one that's going to change your health. Here's a little analogy on how I kind of explain things to my patients. It's very unscientific, but I like it. Uh, semaglutide is a sledgehammer. Trzepatide is more like Michelangelo with a hammer and chisel. You know, trzepatide is often the more elegant medication. Two pathways better tolerated, stronger anti-inflammatory effects, possibly better for lean mass preservation. But when it comes to puber raw appetite suppression, semaglutide often wins. So if a patient comes to me and says, I just need the food noise to stop, semaglutide is frequently the better pick for that specific goal, believe it or not. If you're on semaglutide and it's working, meaning you're you losing half a pound to at most three pounds a week, and you're tolerating the medication, there is no reason to switch just because trazepidite has better average numbers. You are not an average. You are an N of one. Quick note before we get into specific pricing. Everything I just walked you through, the trial data, the side effect profiles, the prescribing framework. It's a few chapters of a 44-chapter book I wrote called the GLP 1 Bible. It covers everything, how these medications work, every side effect and what to do about it, drug interactions your doctor might miss, how to eat and train while you're on treatment, what happens when you stop, the new medications coming down the pipeline, so 44 chapters, over 800 references. It's written for patients, it's not medical journals. The GLP 1 Bible is available for pre-order now at BarrickHealth.com. If you want the full picture, not just the 25-minute version, that's where you'll find it. Alright, let's get into the specific numbers. Here's what the brand name pricing looks like right now as of spring 2026. Oral Wagovy,$149 to$299 per month, depending on the dose, paying cash through Norvo Nordisk's program. Uh injectable Wagovy, that's around$349 per month through NovaCare. Then injectable Zbound, that's going to range$299 to$449 per month, depending on the dose. And that's going to be through LilyDirect. With commercial insurance and a manufacturer's savings card, any of these could drop as low as$25 a month. Sometimes I even see it$25 for three months of medication. Or it could be a prior authorization fight that takes weeks. You know, we'll cover the insurance playbook in some later episodes. And if you have a true needle phobia, I will say oral wagovy is an intriguing option. You know, it's a daily pill, same active ingredient as injectable wagove, now recently FDA approved for weight loss. It does come with some pretty strict timing requirements. You know, empty stomach, small glass of water, wait 30 plus minutes before eating or drinking or taking any other medication. So that's a it's a significant lifestyle consideration. But for patients who genuinely cannot do needles, and believe me, I understand phobias. I have a real deal fear of heights. Like I get it. Sometimes you cannot do a thing. Um having an oral option that actually works changes the equation. Uh, we'll do a full episode on the oral pill, uh, because there is a lot to unpack there. Um, and I get a lot of questions from a lot of patients about the oral pills right now. But I wanted to flag it here because you know it matters for this comparison. On the compounding side, picture is shifting. So, you know, FDA has been tightening restrictions now that the official drug shortages have quote unquote resolved. Uh compounded semaglutide is still widely available and quite affordable for most folks, and compounded torzeptide availability and pricing, it varies a bit, but still pretty consistent right now. Uh, and here's what I need to I need to get something off my chest. So, you know, there is so much fear-mongering on the regulatory side of the compounding world right now. And there's I see so many social media accounts um constantly framing every FDA move as this catastrophe. Uh, because that's what drives clicks. They don't care about your anxiety, they don't care about your health journey, they care about engagement metrics, and they're profiting off of your fear. I do not recommend preemptively switching medications because you're afraid of some regulatory move that might happen. Ask yourself this people have been getting compounded GLP1s for over three years now. Throughout those three years, how high has your anxiety been about losing your access to your terzepatite? And have you actually really lost access to it? For most of you, the answer is the anxiety has been high and the actual disruption has been very close to zero. Looking back, you know, that should tell you something about the gap between what social media predicts and what actually happens. Bear in mind the politicians are well aware that there are millions of patients on compounded medications, and all those patients vote. So they are going to be loath to really make any substantial regulatory moves in the long run. They know they're going to be very, very unpopular. So stay in contact with your provider, have a backup plan, but do not make medical decisions based on fear of a headline that hasn't happened yet. Uh the broader trend is positive, you know, between manufacture direct programs, Trump RX, bringing in, you know, injectable brand name pricing to around$350 a month, and the oral Wagovy launch. Access is improving. Uh, it's better than it's been at any point since these medications hit the market. I remember, you know, three years ago, where you could not find a Wagovy pen across the whole Dagon country. Things are have improved, and I don't see much reason for the fear-mongering that I unfortunately do see quite a bit on social media. The best GLP1 medication is one that works for your body, that you can tolerate, that you can afford, and that you'll actually take consistently. I know that's not the definitive answer that the internet wants, but it is the honest one. Population data points you in a direction. Your body writes the final answer. So trust the data, but trust your experience. Now, I know a lot of you are listening to this thinking, okay, but what if I'm already on one and I want to switch to the other? How do I actually do that? That is the next episode, episode four, switching between semi and ters. When to do it, how to do it, what dose to start at, and what to expect during the transition. And what to do when you've hit a plateau and you're not sure if the answer is a higher dose or a different medicine. It's the most requested topic in my DMs right now, and we're going to cover every angle. Subscribe so you don't miss it. Share this episode with someone who's trying to decide between the two. If you want a doctor who actually has time for you, check out BarrickHealth.com. I'm Dr. Cleet Barrick. We'll see you next week.